Children with precocious puberty are defined as girls with breast development before age 8 years and boys with testicular enlargement before age 9 years (which corresponds to minus 2 standard deviations (SD) compared to the average age of these changes in both sexes). Earlier age at pubertal start has been associated with earlier age at first vaginal bleeding (menarche) in girls and earlier age at voice change in boys, and with long-term consequences, including shorter adult height and psychosocial adverse effects. Although more frequent in certain ethnicities, the prevalence of precocious puberty in girls is constantly increasing worldwide, following the increase in cases of pediatric obesity. Most children with precocious puberty do not present any endocrine, metabolic, neurologic or neurosurgical condition explaining their earlier pubertal start (these cases are defined as “idiopathic” precocious puberty), but extensive work up (including specific hormone measurements and radiological exams) is routinely performed to eliminate such conditions. An important portion of children with precocious puberty will be considered for treatment with puberty-blocking pharmacological agents, without clear evidence that these treatments will increase their adult height.
Late puberty is defined as an absence of breast development by age 13 in girls (or absence of menarche by age 15), and an absence of testicular enlargement before age 14 in boys. This phenomenon is more frequent in boys, in most of which no pathological cause is detected, and these children will end up developing a spontaneous puberty and achieve a normal adult height. Nonetheless, these children are often referred for endocrine evaluation and investigated to eliminate an underlying medical condition.
Given that age at pubertal start in the population follows a Gaussian distribution, 2.3% of normal healthy children will start their puberty at and age below 2 SD below the mean for each sex, and another 2.3% will start their puberty above 2SD above this mean. Defining which children with precocious or late puberty correspond to these 2.3% of the general population is important, since this would avoid unnecessary investigations and treatment in these patients.
Pubertal traits (age at breast development and menarche in girls, testicular enlargement and voice change in boys, age at pubertal growth spurt in both sexes), have a polygenic nature, and an overlapping genetic architecture in boys and girls. It has been estimated that about 50% of variation in age at menarche can be attributed to genetics. Polygenic risk scores (PRS) have been demonstrated to have an improving ability to identify individuals at significantly high/low predisposition towards complex diseases. Therefore, it has become possible to identify individuals who will lie at the extreme distribution of a trait, such as age at menarche in girls or age at voice change in boys.
Therefore, we posit that PRS for age at menarche in girls or age at voice change in boys, in combination with clinical risk factors (such as increased body mass index) may be able to effectively predict children diagnosed as having idiopathic precocious puberty and in which no further investigation or treatment would be required to achieve a normal adult height (within their parental target height). Also, the same scores could identify children in the opposite extreme of the normal distribution, ie children with late puberty.